HIV-1 Amplifies IL-8 Response Of Human Stellate Cells To Gram-Positive Microbial Products Via H4K5 Histone Acetylation

Zhang, L.; Ali, R. O.; Chamroonkul, N.; Tabrizian, P.; Schwartz, M.; Gunasekaran, G.; Schiano, T.; Fiel, M. I.; Ward, S.; Bansal, M. B.

doi:10.1101/2025.05.12.653460

bioRxiv · 10.1101/2025.05.12.653460

HIV-1 Amplifies IL-8 Response Of Human Stellate Cells To Gram-Positive Microbial Products Via H4K5 Histone Acetylation

Zhang, L.·Ali, R. O.·Chamroonkul, N.·Tabrizian, P.·Schwartz, M.·Gunasekaran, G.·Schiano, T.·Fiel, M. I.·Ward, S.·Bansal, M. B.

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Abstract

BackgroundPatients living with human immunodeficiency virus 1 (PLWH) develop accelerated liver fibrosis, but the exact mechanism remains unknown. Activation of hepatic stellate cells (HSCs)--a cornerstone of fibrosis--is influenced by various factors, including viral infection, hepatocellular injury, chronic immune activation, gut barrier dysfunction, and microbial translocation. The role of gram-positive microbial products in human immunodeficiency virus 1 (HIV-1) infection-associated liver inflammation and fibrosis remains poorly understood. This study investigates the effect of lipoteichoic acid (LTA), a major gram-positive bacterial component, on HSCs in the context of HIV-1 infection. MethodsHuman HSCs were isolated from liver tissues of both HIV-1-infected and uninfected individuals undergoing hepatic resection. Inflammatory responses of HSCs to LTA stimulation were measured ex vivo via ELISA before and after HIV-1BaL exposure. Western blotting, ChIP-qPCR and RNA-seq were used to reveal the mechanisms contributing to the IL-8 response to LTA stimulation and HIV-1BaL exposure in HSCs. ResultsLTA modestly induced interleukin-8/CXCL8 (IL-8) production in HSCs, but this response was significantly heightened following HIV-1 exposure. Increased IL-8 levels were also observed in liver tissues from HIV-1-infected patients. In vitro, IL-8 treatment of HSCs elevated -SMA and COL1A1 expression, implicating IL-8 in fibrosis progression in HIV-1 infection. Transcriptomic analysis pointed to histone acetylation as a key regulator of the IL-8 response of HSCs to LTA during HIV-1 infection. Supporting this, the histone deacetylase (HDAC) inhibitor Trichostatin A (TSA) further enhanced IL-8 expression in HIV-1-exposed HSCs. ChIP-qPCR confirmed that acetylation of histone H4K5 facilitated IL-8 promoter transactivation, sensitizing HSCs to LTA under HIV-1 influence. ConclusionsHIV-1 infection primes HSCs for an exaggerated response to LTA, driven by histone acetylation and resulting in elevated IL-8 production--potentially accelerating liver fibrosis in PLWH. Given the persistence of microbial translocation despite effective antiretroviral therapy, these findings highlight the need for targeted interventions to prevent or mitigate liver fibrosis in PLWH.

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Zhang, L., Ali, R. O., Chamroonkul, N., Tabrizian, P., Schwartz, M., Gunasekaran, G., Schiano, T., Fiel, M. I., Ward, S., Bansal, M. B.. 2025-05-15. HIV-1 Amplifies IL-8 Response Of Human Stellate Cells To Gram-Positive Microbial Products Via H4K5 Histone Acetylation. https://doi.org/10.1101/2025.05.12.653460

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